Impact of somatic SWI/SNF alterations on the genomic landscape of pancreatic ductal adenocarcinoma and response to PARP and immune checkpoint inhibitor therapy.
Authors: Heng Tan, Yasmine Baca, Joanne Xiu, Joanita Figueredo, Vaia Florou, Emil Lou, John Marshall, Wafik S. El-Deiry, Wolfgang Michael Korn, Phillip Walker, Davendra Sohal, Igor A. Astsaturov, Michael J. Pishvaian, Nkiruka Ezenwajiaku, Jashodeep Datta, Nipun B. Merchant, Pearl H. Seo, Jonathan C. Trent, Gilberto Lopes, Peter Joel Hosein
Journal: Journal of Clinical Oncology (2022)

e16289 Background: The SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complex is an adenosine triphosphate (ATP)-dependent group of proteins that controls the accessibility of transcription factors to DNA and is a dynamic epigenetic regulator of gene expression. This system is deranged in about 14% of pancreatic ductal adenocarcinoma (PDAC) patients (pts). A recent report suggested that SWI/SNF alterations are associated with response to immune checkpoint inhibitors (ICIs). Herein, we investigate the relationship between SWI/SNF alterations and genomic instability, prognosis and response to PARP inhibitors and ICIs. Methods: Tumor molecular profiling was performed on PDAC FFPE samples by NextGen Sequencing on DNA (592 genes or WES) and RNA (WTS) at Caris Life Sciences (Phoenix, AZ). MSI/MMR status was determined by IHC, NGS and fragment analysis. Tumor mutational burden high (TMB-H) was determined by a cutoff of 10mut/MB, PD-L1 was tested by IHC (SP142) with a cutoff of 2+, 5%. SWI/SNF mutant tumors (MT) were compared to wild-type (WT), and significance was determined by X 2 or Fisher-Exact and p adjusted for multiple comparisons (q) of &lt; 0.05 (Benjamini-Hochberg correction). Real-world overall survival was obtained from insurance claims data and calculated from tissue collection to last contact; time on treatment (TOT) was calculated from treatment start to finish and compared by the Kaplan-Meier test. Results: Among 5075 PDAC tumors, 311 (6.1%) harbored SWI/SNF alterations (186 ARID1A-mutant, 60 PBRM1, 65 SMARCA4 and 12 SMARCB1). The proportion with SWI/SNF alterations in MSI-H tumors (23/53 or 43%) was higher than MSS (287/4922 or 5.8%, p &lt; 0.001). Since MSI-H PDAC have distinct genomic behavior compared to MSS, MSS tumors were analyzed separately. TMB-H (8.3% vs. 1.2%) and PD-L1-H (23% vs. 15%) were more prevalent in MT than WT (q &lt; 0.05) but not different in MSS tumors (TMB-H: 2.9% vs. 0.6%, q = 0.09; PD-L1: 21.4% vs. 15.4%, q = 0.3). Among the 2268 WES-tested tumors, gLOH-high was not different in MT vs WT (9% vs. 12%, q = 1) in all or in MSS tumors (9.7% vs 11.9%, q = 1). Among the 3728 pts with outcome data, MT pts had worse prognosis (HR = 0.78, 95% CI [0.70-0.87], p &lt; 0.00001), similarly in MSS cohort (HR = 0.734, [ 0.66-0.82], p &lt; 0.00001). Among 50 PARPi-treated pts, no TOT difference was seen between MT vs WT (HR = 0.913, [0.309-2.701], p = 0.9), similarly in MSS pts (HR = 1.104 [0.426–2.86], p = 0.9). In the 38 ICI-treated pts, no difference was seen in TOT between MT vs WT (HR = 1.42 [0.73-2.8], p = 0.3], similarly in MSS pts (HR 1.175 [0.524–2.636], p = 0.7). Conclusions: In this real-world database, SWI/SNF alterations were associated with a significantly worse prognosis. There was no association with increased genomic instability of PDAC tumors, and in the cases with linked treatment data, there was no association with response to PARPi’s or ICI’s.